1. Field of the Invention
This invention relates to spectrophotometric methods and apparatus for quantitatively determining the degree of oxygen saturation of the hemoglobin in the blood within a body part or organ, and in particular pertains to determination of the percent oxygen saturation of intra-cerebral blood.
2. Description of the Related Art
Background
It is generally known that metabolism and more particularly oxygen sufficiency and adequacy of utilization are parameters of fundamental importance in assessing the function of any body organ. This is made self-evident when one considers that the energy provision for tissue function is underwritten for better than 90 percent by oxidative reactions involving the reduction of O2 to H2O. In the absence of sufficient oxygen, this process becomes impaired with a corresponding impairment in organ function. Also recognized is the fact that an excess of oxygen also impairs organ function. For ease of explanation, the description to follow is based primarily on considering the effect of an insufficiency rather than an excess of oxygen.
In instances of extensive oxygen deprivation, over a period of time the organ loses viability and as a result the individual often has the same fate, especially if that organ is the brain. Although all organs are adversely affected by oxygen insufficiency, perhaps the problem is most acute in the case of the brain because of its complete dependence on oxidative metabolism for proper function and viability. For example, an absence of oxygen in the brain for more than a dozen seconds produces dysfunction and an absence for longer than a few minutes spells irreversible damage. A less acute impairment of oxygen availability leads to a gradual loss in brain function, especially with respect to the higher centers of the cerebral cortex. An excess of oxygen will also adversely affect the brain. For example, a neo-natal patient may well go blind by reason of excess oxygen.
Because of the vital role that oxygen sufficiency plays in human physiology, intensive efforts have been made over the years to measure this parameter in various organs and most particularly in connection with the assessment of brain and heart function. Numerous spectrophotometric methods exist for non-invasive, continuous, monitoring of metabolism in a body organ both by use of transillumination and reflectance. By xe2x80x9ctransilluminationxe2x80x9d is meant the practice of passing light through a body organ and by xe2x80x9creflectancexe2x80x9d is meant the practice of diffusely reflecting light from a body organ. These methods are used primarily as instruments to determine the fraction of total hemoglobin in blood that carries oxygen. By common agreement, oxygenated hemoglobin is designated HbO2 whereas Hb refers to the deoxygenated form and total hemoglobin is abbreviated Hbt.
For about half a century, physicians have relied on measurements of the percentage of the hemoglobin in the blood that is saturated with oxygen (the xe2x80x9c% O2 Satxe2x80x9d) in attempts to assess the oxygenation of tissues. The introduction of this parameter, measured in blood samples drawn from the patient, was a great step forward over the visual observation of the color of various tissues (skin, gums, fingernail beds, etc.)
By common practice, arterial blood samples are used for the assessment of the % O2 Sat. Venous blood samples vary unpredictably depending on the metabolic activity of the organ(s) drained by the donor vein. Even in a given organ blood can be channeled through bypass vessels that can and do vary in their dilation or constriction thus changing the fractions of the blood in the nutritive and in the bypass circulations. Mixed central venous blood as taken from the right side of the heart is difficult to obtain and is therefore not routinely available. It also lacks the specificity required for the assessment of oxygenation status of individual organs.
Although arterial blood has the identical % O2 Sat throughout the body, the parameter does not predict adequacy of organ oxygenation. Matters are complicated by such unknowns as the rate of blood flow, the pH and the CO2 content and by the amount of hemoglobin in the blood which affects the total amount of O2 that can be transported. Instrumentation has been devised to measure these complicating factors in the blood samples and the use of radio-active molecules has been introduced to measure blood flow in certain organs, especially the brain.
In addition for the spectrophotometric measurements of blood in intact tissues, it should be recognized that, depending on the oxygen supply, the oxidative metabolic enzyme cytochrome c oxidase has an absorption spectrum in the spectral region used (750-950 nm). Corrections for this problem have not been introduced in the present art.
Starting in the 1930""s, many attempts were made to determine oxygenation status non-invasively by optical means, i.e. to substitute instrumentation for the physicians eye. None of these instruments was truly successful or affordable in the routine clinical setting until introduction of the so-called pulse oximeter in the early 1980""s which provides arterial % O2 Sat values in a non-invasive manner. The technique depends on measuring the color of new blood entering the field of observation with each heartbeat. Typically the finger tip, earlobe or toe is transilluminated with two wavelengths, one in the visible (VIS) and one in the near infrared (NIR) range of the spectrum. Alternatively, reflectance optics may be used as described in U.S. Pat. No. 5.692,503. The stable background light signal is subtracted from the measurement made during the pulse of new blood arriving after the heartbeat. Several U.S. patents teach the pulsatile approach by either transillumination or reflectance (see for example U.S. Pat. No. 5,337,745) for either hemoglobin determinations or concentrations of other blood components such as glucose. Thus this oxygenation measurement again reports on the % O2 Sat (or on concentrations of other components) in the arterial blood. The measurement therefore reports only on the quality of pulmonary function in oxygenating the blood. No information is present about oxygen sufficiency in the tissue(s).
With pulse oximetry, all the drawbacks and limitations of the arterial sampling techniques are still present and in fact are exacerbated by the absence of a sample in which hemoglobin and CO2 content and the pH can be measured. Also, the technique requires firm pulsatile flow which is often not present in seriously ill patients and is frequently not measurable in deeper tissue such as the brain.
It can thus be seen that the field of physiological monitoring of patient oxygenation status requires a fundamentally different approach that provides information on the steady state of tissue oxygenation rather than being limited to the efficacy of pulmonary function.
A further aspect of the prior art to be appreciated is the application of the so-called Beer-Lambert law for determining concentrations of light absorbing molecules by measuring circuit parameters from two conditions, for instance of the light being transmitted in the absence of these molecules and in their presence or alternatively the light intensity measured directly without passing through the test subject as compared to the light being transmitted through the test subject. Various literature sources discuss how this law is applied, one such source being U.S. Pat. No. 3,923,403 and another being the above-mentioned U.S. Pat. No. 5.692,503.
An appreciation of how various combinations of measuring and reference wavelengths have been applied in the prior art for physiological measurements is also deemed useful to an appreciation of the present invention. Typically a single xe2x80x9creferencexe2x80x9d wavelength is used for samples that have a tendency to scatter light. The data from a measuring wavelength is then compared to those from the reference. The former is commonly chosen to be that of the absorption peak whereas the reference is chosen at a more neutral wavelength. The use of two reference wavelengths straddling the measuring one is advocated in U.S. Pat. Nos. 5,377,674 and 5,692,503 and is shown in an article by Jxc3x6bsis, Keizer, LaMana and Rosenthal published in 1977 in the Journal of Applied Physiology, Volume 43, pages 858 to 872. U.S. Pat. Nos. 4,281,645; 4,697,593; 4,997,769; 4,805,623; and 5,337,745; may be referred to for additional background examples of various singular and multiple wavelength combinations, some of which reside within the near infrared region of interest to the present invention. While the prior art thus does provide means for extra and/or intra-corporeal detection and measuring of blood oxygenation, it can be noted with reference to all such prior art that none of the methods or apparatus of the prior art provide apparatus and methods for intra-corporeal, in vivo, in situ, detecting and measuring the degree of oxygenation of the hemoglobin in the blood within a tissue or organ in the manner of the present invention and independent of the path length. The disclosure of the foregoing and all other patents and publications referred to herein are incorporated herein by reference.
Prior Art Practices Specifically Related To Measuring Oxygen Saturation In Tissue
Analyzing tissue oxygenation by hemoglobin oxygen saturation requires choosing the wavelength range to be utilized and accurate measurement of in vivo spectra of oxygenated and deoxygenated tissue in that range. In this regard, a part of the near infrared (NIR) region (i.e. 700 nm to 950 nm) is favored over the better known visible range (450 to 700nm) because of the muted light scattering properties of the longer wavelengths. Nevertheless, measurements are also possible in the extended range of 600 to 1300 nm as disclosed below. In addition, only three oxygen sensitive molecules (hemoglobin, Hb; myoglobin, Mb; and cytochrome c oxidase previously known as cytochrome aa3 and abbreviated cyt c ox), absorb light of these wavelengths. Hemoglobin and myoglobin have practically identical NIR absorption spectra, both in their oxygenated (HbO2 and MbO2) and de-oxygenated (Hb and Mb) forms. Thus, the NIR measurements are of HbO2+MbO2 and of Hb+Mb respectively. During cerebral monitoring the myoglobin contribution is trivial to absent since it only occurs in muscle cells. However, when monitoring muscle tissue, the Mb and MbO2 contributions are significant. In cerebral measurements the cyt c ox contribution to the total optical signal can vary and under certain pathological circumstances may be sufficiently large to produce a substantial error in the hemoglobin determinations.
Non-invasive determination of the concentration of blood components Hb and HbO2 in intact biological tissues and body organs utilizing spectrophotometry is complicated by the fact that these measurements are made in a turbid, optically impure, multiple-component environment. In such an environment, particularly in body tissues and organs, light scattering, even at NIR wavelengths, generally results in greater, sometimes much greater, loss of light than is lost by actual absorption of the incident light by the various light absorbing molecular species present. In addition, scattering increases the path the photons travel from the input point to the point of collection. This defeats use of the Beer-Lambert law which requires exact knowledge of the optical path length.
The in vivo spectra differ from the in vitro spectra of purified hemoglobin due to light scattering by the tissue, which is not the same at all wavelengths, not even in the NIR. The shorter the wavelength, the more intense light scattering becomes. This has two consequences: photons at shorter wavelengths are more easily lost by being scattered away from the detector and, photons of shorter wavelength that finally do reach the detector have traversed a longer path than the longer wavelength photons since the former are scattered more frequently. This results in a greater degree of absorption of lower wave-length photons and thus to a skewing of the absorption spectrum. Various meansxe2x80x94physical, chemical and computational - have been introduced to overcome problems such as those described. Such problems are greatly exacerbated however when an attempt is made to measure the O2 saturation of the blood within large organs (the brain, the heart, etc.) rather than small thin ones such as ear lobes, finger tips, and the like.
Review Of Method For Quantitative Analysis By Spectrophotomety
The Beer-Lambert law equation defines the relationship between light absorption, absorber (solute) concentration, extinction co-efficient and optical path length as follows:
log Io/I=dxc2x7exc2x7 concentration, where:
Io is the intensity of the light transmitted through the medium (solvent) in the absence of the absorber to be measured;
I is the intensity of transmitted light in the presence of the absorber;
Log Io/I is variously called the Absorbance, Absorbancy or Optical Density;
d is the length of the optical path through the sample;
e is the molar (or milli-molar or micro-molar) extinction co-efficient, i.e. the light loss incurred (the absorption measured) during passage through a one molar (a milli or a micro-molar) solution over 1 cm; dimension: molesxc3x97literxe2x88x921xc3x97cmxe2x88x921).
Once the optical density is determined of a solution of a single, known absorber with known e in a vessel of known pathlength, the concentration of that solute can be calculated.
Traditionally, extinction coefficients are determined by analyzing the light losses when beams of mono-chromatic light are transmitted through a vessel (cuvette) of known path length containing a clear (non-opalescent, non-scattering) solution of known concentration. At different wavelengths the extinction coefficients will vary; a graphic representation of these coefficients on a wavelength scale is called the absorption spectrum of the absorbing compound.
In nature clear, non-scattering solutions are rare exceptions. Spectrophotometry of natural entities must therefore cope with substantial light scattering of incident light. This causes distinct problems as previously referred to: (a) light is not only lost by absorption but also by being scattered away from its path to the detector; and (b) light that does reach the detector will have traveled a random, helter-skelter route of unknown path length as it is scattered multiple times before emanating from the object. This is an especially serious limitation for large, dense objects, from which only a dim light can be perceived, as is the case for the human head and brain.
The degree of light scattering and therefore the optical path elongation is due to a complex combination of the wavelength, the geometric length of the optical path, the shape and size of the scattering particles and the difference in the indices of refraction between the solvent and the particles, which in biological samples are more glazy than specularly reflective. In addition, this difference varies with the metabolic state because of shifts of ions and water in the cells. Thus, it is not possible to construct a comprehensive mathematical expression to correct with sufficient precision for the differences between the geometric and actual optical path length traversed in vivo.
Previous oxygen saturation determination methods in body parts generally required measurements through only thin body parts such as the ear lobe or the finger tip in which multiple scattering is sufficiently small so as not to affect significantly the absorption spectra of hemoglobin and the observed concentrations of Hb and HbO2. In significant contrast, determining the actual path length traveled by the radiation through a longer body part requires complex and expensive biophysical instrumentation and difficult experimentation. In the case of human infant""s heads, the results have been found to be about 3-6 times greater than the path length determined by simply measuring the width of the body part between the points of illumination and detection, i.e. the geometric path length. Therefore, determining the actual path length taken by the radiation through a relatively long body part, is complicated and subject to error and unreliable when trying to determine the oxygen saturation of the blood. In the application of optical monitoring to larger solid organs, it is possible to utilize the back scattering of light out of the tissue by so-called diffuse reflectance. In this case, the input and detection points are several centimeters apart on the same surface of the solid organ, as was described earlier in U.S. Pat. 4,281,645.
From the foregoing description and other description to follow, the shortcomings in the prior art methods and apparatus for determining oxygen saturation of the hemoglobin in the blood within a body organ can be characterized as follows:
(a) they require determination of actual concentrations of Hb and HbO2;
(b) use of the Beer-Lambert law is defeated since use of this law requires exact knowledge of the optical path length;
(c) as the invention recognizes, path length correction factors are quite variable, should be determined from case to case and should be continuously updated for changes in metabolism, but neither is possible with the prior art;
(d) the variable degree of absorption by cytochrome c oxidase is not corrected for;
(e) as the invention further recognizes, light scattering introduces significant deviations from standard extinction coefficients; deviations that differ depending on wavelength but in the prior art no accounting is made for this skewing of the absorption spectra;
(f) no means or method is provided for distinguishing scattering losses from absorption losses;
(g) differences in optical path length created by large differences in measuring wavelengths and therefore in wavelength dependent scattering are not corrected for;
(h) previous apparatus, especially those for pulse oximetry, used to determine % O2 Sat of arterial blood lack means or method for mitigating effects of distortion by scattering;
(i) no provision is made for entering the light of various wavelengths homogeneously into the body organ at a single point of entry;
(j) the adequacy of organ oxygenation is not revealed since the cyt c ox is not monitored and therefore not corrected for; and
(k) firm pulsatile flow is required.
Objects of Invention
It is therefore an object of this invention to provide a method and apparatus for determination of the degree of oxygen saturation of the hemoglobin in the blood within tissues and organs (the xe2x80x9c% Tissue Blood O2 Satxe2x80x9d) such as the head or other organ or body parts, such as the heart or muscle tissue which minimizes the error due to the scattering of light.
It is another object of this invention to eliminate the error contributed by cytochrome c oxidase.
It is a further object of this invention to provide a method and apparatus for determination of the described degree of oxygen saturation in which knowledge of the optical path length and concentrations of Hb and HbO2 are not needed.
It is another object of this invention to provide a method and apparatus for determination of the described degree of oxygen saturation in which the skewing of absorption spectra has been accounted for.
It is a further object of this invention to provide a method and apparatus for determination of the described degree of oxygen saturation in which the effect of scattering and scattering changes is minimized.
It is also an object of this invention to provide a method and apparatus which permit in situ extinction coefficients to be utilized in making a determination of the degree of oxygen saturation of the hemoglobin in the blood within a body organ tissue.
It is a further object of the invention to furnish a device by which the presented wavelengths are homogeneously entered into the body part or organ at the same point.
It is also an object of this invention to eliminate the necessity to assign pathlength correction factors by which the geometrical distance between input and receiver should be multiplied to approximate the optical pathlength.
Other objects and advantages will be more fully apparent from the following disclosure and appended claims.
In general, the shortcomings of the prior art systems and methods for determining the degree of oxygen saturation of the hemoglobin in the blood within a body organ are overcome, circumvented or mitigated by the system and method of the invention which are characterized by the following important features:
1. The method of the invention causes subtraction of the absorption signal at the Hb/HbO2 isosbestic wavelength (see definition below) from the absorption signals at the other wavelengths; the differences are then utilized to create multiple simultaneous equations which can be solved for the multiple absorbing components;
2. In the case of unavailability of a laser at the isosbestic wavelength, the method and apparatus of the invention permits use of two or more lasers producing wavelengths of light near the isosbestic one, preferably straddling the isosbestic one.
3. In the method and apparatus of the invention, there is a realization of the ability to deduce oxygen saturation of the blood in the tissue without determining the concentrations of the two forms of the hemoglobin;
4. The invention method provides correction for or solution of the redox state of cyt c ox;
5. The apparatus and method of the invention obviates the need to determine scattering or scattering changes to prevent errors by changes in metabolism during the monitoring period;
6. The method of the invention requires at least three wavelengths - one isosbestic and two measuring onesxe2x80x94while permitting addition of a fourth (or more) measuring wavelengths to simplify application of the invention or cope with limitations in availability of lasers with preferred wavelength output; and
7. The method and apparatus of the invention also prevents errors caused by local arterial and venous blood vessels through use of a light mixer or homogenizer with a single aperture to enter light into the body.
More specifically, the method and apparatus of the invention provide means for intra-corporeal, in-vivo, in-situ, detecting and measuring the degree of hemoglobin oxygenation in tissue independent of the optical path length. The method and apparatus of the invention ascertains the clinically important physiological parameter xe2x80x9c% TissueO2Satxe2x80x9d (i.e. percent of hemoglobin in the blood within tissues in a body part that is oxygenated). In this regard the method and apparatus of the invention determines the ratio of HbO2 to (HbO2+Hb) without the need for determining the actual concentrations of Hb and HbO2.
Where the term xe2x80x9cbody partxe2x80x9d is used in the description and is later used in the claims in reference to the invention, it will be understood that such term is meant to refer to a part of a human, animal or other living body exhibiting active oxidative metabolism. For example, with respect to a human body, such xe2x80x9cpartxe2x80x9d might, for example, be the hand, heart, head, kidney, liver or tumor of an individual being tested for percent oxygen saturation of the hemoglobin in the blood within such part. The heart, head, kidney and liver by way of example are each also typically recognized as being an xe2x80x9corganxe2x80x9d as such term is used in the description. The term xe2x80x9ctissuexe2x80x9d is also used in the description to refer to a component of such body part or organ.
In its preferred embodiment, the present invention utilizes a single reference wavelength and two or more measuring wavelengths. The strength of the received signal of the reference wavelength radiation is subtracted from those of the two or more measuring wavelengths.
The method and apparatus of the invention, unlike the practices of the prior art, introduces a means to assess accurately the degree of oxygenation of the blood within an organ notwithstanding the unknown pathlength elongation and increases the reliability of the measurements by correcting for the skewing of absorption spectra and for variable absorbance contributions of cytochrome c oxidase.
In the preferred embodiment of the invention, light at multiple wavelengths, typically three, four or more different wavelengths, is defocussed and preferably mixed before being entered into the body organ or tissue at exactly the same location on that organ. The absorption at the isosbestic (reference) wavelength of the oxyhemoglobin and deoxyhemoglobin components, (i.e. where the absorption is the same for the two forms of the molecule) is subtracted from the absorption at two or more other (measuring) wavelengths. Thus, the first (reference) wavelength is preferably chosen to be at or near (within about 10 nm) the isosbestic point for the two components (Hb and HbO2), which is about 815 nm (between 810-820 nm). In the three wavelength technique, the two other wavelengths are preferably in the 780 nm and 900 nm regions. When three measuring wavelengths are used, they are preferably in the ranges of 750-785, 860-875 and 895-915 nm, respectively. Visible wavelengths in the red region of the visible spectrum (600 to 700 nm) and the farther NIR region of 1100 to 1300 nm can also be employed.
The total light loss at the reference wavelength (i.e. by scattering and by its absorption by tissue components, fib and HbO2 primarily) is subtracted from the total light loss at each of the other wavelengths. The subtraction removes the effect of scattering, assuming scattering across the NIR range of interest (750 nm to 950 nm) is nearly constant per wavelength difference. As later explained, the residual effect that scattering has on the skewing of the absorption spectra of hemoglobin and cyt c ox is corrected for by using their in vivo, in situ spectra rather than their in vitro spectra.
Using the differences between the detected electronic signals of the different wavelengths rather than the total signals (scattering loss plus absorption loss), the amount of each of the two components, i.e. Hb and HbO2, may be determined. Subsequently the ratio of the amounts is used to obtain a dimensionless number corresponding to oxygen saturation in terms of % Tissue Blood Oxygen Saturation, i.e. for cerebral tissue % CBOS. Thus, the concentration of Hb and HbO2 do not need to be determined. This circumvents the need to determine the optical pathlength in the tissue and avoids further errors when this pathlength changes.
The apparatus of the invention provides a source of multiple wavelengths, a device for mixing the wavelengths, received directly from the sources, prior to entering the light into the body organ, means for directing the mixed wavelengths at a single point of entry, a detector for measuring the input intensity of each wavelength and one for measuring its intensity after its attenuation by the tissue and a processor for processing signals related to the absorption to produce the number referred to above (% Tissue Blood O2 Sat) according to the method of the invention.